Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1995-03-21
1999-06-08
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C07D47340
Patent
active
059105895
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for the preparation of a compound useful as an intermediate in the preparation of pharmaceutical compounds. The compound 2-amino-6-chloropurine of formula (I): ##STR1## is a useful intermediate in the preparation of nucleoside analogue antiviral agents, such as penciclovir and famciclovir, described in EP-A-141927 (Example 1) and EP-A-182024 (Example 2). The intermediate is 9-substituted with an appropriate side chain precursor, followed by .Conversion of the 6-chloro moiety to a hydroxy (a guanine) or hydrogen (a 2-aminopurine).
EP-A-203685 (Beecham Group p.l.c.) describes a process for preparing a compound of formula (I) as hereinbefore defined, which process comprises reacting guanine with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions. EP-A-433846 (Hoechst
Aktiengesellschaft) describes a corresponding process for preparing the 2-acylated derivative, involving chlorination of 2,9-diacylguanine and subsequent removal of the 9-acyl group by hydrolysis.
The reaction is preferably carried out in a polar inert organic solvent such as acetonitrile, tetrahydrofuran, dioxan, nitromethane, diglyme or dimethoxyethane. Acetonitrile is highly preferred.
Suitable phase transfer catalysts include tetrasubstituted ammonium chlorides. Examples of ammonium substituents include C.sub.2-12 alkyl, usually C.sub.2-4 alkyl, or phenyl or benzyl. Other possible phase transfer catalysts include tetra-substituted phosphonium chlorides wherein examples of the substitutents are as defined above for ammonium chlorides. The preferred phase transfer catalyst used was tetraethylammonium chloride.
The phase-transfer catalyst is preferably present in an amount of from 1 to 3 equivalents of the compound of formula (II) and preferably from 1 to 2 equivalents.
A preferred chlorinating agent it phosphorus oxychloride.
Preferably the chlorinating agent is present in an amount of from 2-10 preferably from 3-6 molar equivalents of the compound of formula (I).
The reaction may be effected in the presence of a weak base, such as a tertiary amine, for example N,N-dimethylaniline or diethylaniline. The base is usually present in an approximately molar equivalent amount with respect to the compound of formula (I). Alternatively, a catalytic amount of water may be added to the reaction mixture. When acetonitrile is the solvent, added base is not necessary.
The reaction is preferably carried out at an elevated temperature of from 30-100.degree. C., most preferably under reflux and/or with ultrasonication at 60-70.degree. C.
Preferably the reaction is allowed to proceed for a period of greater than half an hour, usually less than 30 hours.
Surprisingly, we have now discovered that the preferred phase transfer catalyst is methyltriethylammonium chloride (TEMAC).
Accordingly, the present invention provides a process for preparing 2-amino-6-chloropurine or a 2-acylated derivative thereof, which process comprises reacting guanine or a 2,9-diacylated derivative thereof, with a chlorinating agent in the presence of TEMAC, and thereafter when necessary, removing the 9-acyl group by hydrolysis.
All other aspects of the process are as described in EP-A-203685 and EP-A-433846.
The following examples illustrate the-invention.
EXAMPLE 1
(2-Amino-6-chloropurine)
A mixture of guanine (22.7 g, 0.15 mol), methyltriethylammonium chloride (TEMAC) (45.5 g, 0.3 mol), phosphorus oxychloride (82.6 ml, 0.9 mol) and acetonitrile (67 ml) was heated at 60.degree. C. with stirring for 6 hours and then cooled to 10.degree. C. The solid material was filtered off and suspended in water (300 mls). The aqueous mixture was brought to alkaline pH with aqueous sodium hydroxide to achieve dissolution and powdered carbon (6.8 g) added. The mixture was stirred for 1 hour and then filtered to remove the carbon. Acetone (72 mls) was added and then the pH reduced to 7 with dilute hydrochloric acid. The product was filtered off, washed with acetone/water (50:50 mixture, 50 mls), water (50 mls), acetone/water
REFERENCES:
patent: 4736029 (1988-04-01), Harnden et al.
patent: 5075445 (1991-12-01), Jarvest et al.
patent: 5216161 (1993-06-01), Hanson
patent: 5389637 (1995-02-01), Igi
patent: 5434263 (1995-07-01), Hertzsch
Secrist, J Med Chem 28, 1740 (1985).
Translation of EP 433 845 (1991).
Berch Mark L.
Dinner Dara L.
Kinzig Charles
SmithKline Beecham p.l.c.
Venetianer Stephen
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